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    Summary
    EudraCT Number:2018-002722-22
    Sponsor's Protocol Code Number:H2020/755094/2017/IT-01
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-02-05
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2018-002722-22
    A.3Full title of the trial
    Safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS)
    Sicherheit und Wirksamkeit von Tauroursodeoxycholsäure (TUDCA) als Zusatztherapie bei Patienten, die an amyotropher Lateralsklerose (ALS) leiden
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and efficacy of a treatment with tauroursodeoxycholic acid (TUDCA) on top of riluzole in patients affected by amyotrophic lateral sclerosis (ALS)
    A.3.2Name or abbreviated title of the trial where available
    TUDCA-ALS
    A.4.1Sponsor's protocol code numberH2020/755094/2017/IT-01
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03800524
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorHumanitas Mirasole SpA
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEuropean Commission
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIstituto Clinico Humanitas
    B.5.2Functional name of contact pointUfficio Sperimentazioni Cliniche
    B.5.3 Address:
    B.5.3.1Street AddressVia A. Manzoni 56
    B.5.3.2Town/ cityRozzano
    B.5.3.3Post code20089
    B.5.3.4CountryItaly
    B.5.4Telephone number00390282244056
    B.5.6E-mailpaola.maisola@humanitas.it
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name TUDCABIL
    D.2.1.1.2Name of the Marketing Authorisation holderBruschettini s.r.l.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/17/1844
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNtauroursodeoxycholic acid
    D.3.9.1CAS number 14605-22-2
    D.3.9.2Current sponsor codeTUDCA
    D.3.9.3Other descriptive nameTAUROURSODEOXYCHOLIC ACID
    D.3.9.4EV Substance CodeSUB20887
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Amyotrophic Lateral Sclerosis (ALS)
    E.1.1.1Medical condition in easily understood language
    amyotrophic lateral sclerosis
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10002026
    E.1.2Term Amyotrophic lateral sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To asses the efficacy of TUDCA in slowing disease prograssion in patients with ALS
    during the treatment period compared to the lead-in phase as measured by ALSFRS-R..
    E.2.2Secondary objectives of the trial
    - To assess the efficacy of TUDCA in slowing disease progression and functional
    impairment in patients with ALS, as measured by the survival time, the ALSAQ-40
    questionnaire, FVC, the EQ-5D, and muscle force
    - To assess the long term safety and tolerability of TUDCA for up to 18 months in
    patients with ALS.
    The exploratory objectives of this study are:
    - To evaluate the effect of TUDCA on possible biomarkers: CSF and serum neurofilament
    levels, serum MMP-9 expression, and plasma creatinine levels.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    open label extension
    E.3Principal inclusion criteria
    1. Probable laboratory-supported, probable, or definite ALS, as defined by El Escorial Revised ALS diagnostic criteria at screening visit (month -3)
    2. Disease duration ≤ 18 months at screening visit (month -3)
    3. Able to perform reproducible pulmonary function tests at screening visit (month -3)
    4. Forced vital capacity or slow vital capacity ≥70% of normal at screening visit (month -3)
    5. Stable on riluzole treatment for 3 months in the lead-in period
    6. Signed informed consent at screening visit (month -3)
    1. Laborgestützte, wahrscheinliche oder definitive Diagnose der ALS nach den revidierten El-Escorial-Diagnosekriterien für ALS beim Screening-Besuch (M-3)
    2. Dauer der Erkrankung ≤ 18 Monate beim Screening-Besuch (M-3)
    3. Fähigkeit zur Durchführung reproduzierbarer Lungenfunkti-onstests beim Screening-Besuch (M-3)
    4. FVC oder SVC ≥ 70 % des Normalwertes beim Screening-Besuch (M-3)
    5. Stabiles Behandlungsregime mit Riluzol über 3 Monate in der Einleitungsphase (Lead-in)
    6. Unterzeichnete Einwilligung nach erfolgter Patienteninformati-on (informierte Einwilligung) beim Screening-Besuch (M-3)
    E.4Principal exclusion criteria
    1. Treatment with edaravone or other unaccepted concomitant therapy (as per section 8)
    2. Other causes of neuromuscular weakness
    3. Presence of other neurodegenerative diseases
    4. Significant cognitive impairment, clinical dementia or psychiatric illness
    5. Severe cardiac or pulmonary disease
    6. Other diseases precluding functional assessments
    7. Other life-threatening diseases
    8. Any use of non-invasive ventilation (e.g. continuous positive airway pressure, non-invasive bi-level positive airway pressure or non-invasive volume ventilation) for any portion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementation
    9. Gastrointestinal disorder that is likely to impair absorption of study drug from the gastrointestinal tract
    10. Has taken any investigational study drug within 30 days or five half-lives of the prior agent, whichever is longer, prior to dosing
    11. Any clinically significant laboratory abnormality
    12. Other concurrent investigational medications
    13. Active peptic ulcer
    14. Previous surgery or infections of small intestine
    15. Patients unable to easily swallow the treatment pills
    16. Acute inflammation of the gallbladder or bile ducts
    17. Occurrence of frequent biliary colic, biliary infections, severe pancreatic abnormalities
    18. Bile duct obstruction, calcified X-ray opaque gallstones and reduced mobility of the gallbladder
    19. Subjects who weigh 88 lbs (40 kg) or less
    20. Aspartate aminotransferase or alanine aminotransferase concentrations more than 3 times the upper limit of normal
    21. Creatinine clearance 50 ml/min or less
    22. Any clinically significant neurological, haematological, autoimmune, endocrine, cardiovascular, neo-plastic, renal, gastrointestinal, or other disorder that, in the Investigator's opinion, could in-terfere with the subject's participation in the study, place the subject at increased risk, or con-found interpretation of study results
    23. Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive TUDCA or that the subject is unable or unlikely to comply with the dosing schedule or study evaluations
    24. The patient of reproductive potential is sexually active and is not willing to use highly effective contraception during the study and up to 90 days after the day of last dose (see Contraceptive Guidance in Appendix A)
    25. The patient is pregnant or breast feeding
    440 Patienten beiderlei Geschlechts im Alter von 18 bis 80 Jahren (einschließlich)
    Einschlusskriterien:
    1. Laborgestützte, wahrscheinliche oder definitive Diagnose der ALS nach den revidierten El-Escorial-Diagnosekriterien für ALS beim Screening-Besuch (M-3)
    2. Dauer der Erkrankung ≤ 18 Monate beim Screening-Besuch (M-3)
    3. Fähigkeit zur Durchführung reproduzierbarer Lungenfunktionstests beim Screening-Besuch (M-3)
    4. FVC oder SVC ≥ 70 % des Normalwertes beim Screening-Besuch (M-3)
    5. Stabiles Behandlungsregime mit Riluzol über 3 Monate in der Einleitungsphase (Lead-in)
    6. Unterzeichnete Einwilligung nach erfolgter Patienteninformation (informierte Einwilligung) beim Screening-Besuch (M-3)

    Ausschlusskriterien:
    1. Behandlung mit Edaravon oder einer anderen nicht genehmigten Begleittherapie (Substanzen, die die Aufnahme von Gallensäure im Darm hemmen; Antazida, die Aluminiumhydroxid und/oder Smectit enthalten; Östrogene und Mittel, die den Serumcholesterinspiegel senken; Medikamente, die die biliäre Ausscheidung von Cholesterin erhöhen; die Leber schädigende Arzneimittel)
    2. Andere Ursachen für neuromuskuläre Schwäche
    3. Bestehende andere neurodegenerative Erkrankungen
    4. Signifikante kognitive Beeinträchtigungen, klinische Demenz oder psychiatrische Erkrankungen
    5. Schwere Herz- oder Lungenerkrankungen
    6. Andere Krankheiten, die eine funktionelle Beurteilung ausschließen
    7. Andere lebensbedrohliche Krankheiten
    8. Jede Anwendung einer nicht-invasiven Beatmung über einen beliebigen Zeitraum des Tages oder einer mechanischen Beatmung durch Tracheotomie oder jede Form der Sauerstoffzufuhr
    9. Magen-Darm-Erkrankungen, die die Aufnahme des Prüfpräparats beeinträchtigen können
    10. Einnahme eines Prüfpräparats in einem Zeitraum von 30 Tagen oder fünf Halbwertszeiten des Wirkstoffs (je nachdem welche Zeitspanne länger ist) vor der ersten Dosierung in dieser Studie
    11. Irgendwelche klinisch signifikanten Abweichungen der Laborwerte
    12. Andere begleitende experimentelle Arzneimittel
    13. Aktives peptisches Ulkus
    14. Frühere Operationen oder Infektionen des Dünndarms
    15. Patienten die zum die Tabletten des Prüfmedikaments nicht leicht schlucken können
    16. Akute Entzündung der Gallenblase oder der Gallengänge
    17. Häufiges Auftreten von Gallenkoliken, Gallenwegsinfektionen, schweren Anomalien der Bauchspeicheldrüse
    18. Gallengangsobstruktion, verkalkte röntgentransparente Gallensteine und verminderte Beweglichkeit der Gallenblase
    19. Personen mit einem Körpergewicht von 40 kg oder weniger
    20. Aspartat-Aminotransferase- oder Alanin-Aminotransferase-Konzentrationen, die mehr als das Dreifache der Obergrenze des Normalbereichs betragen
    21. Kreatinin-Clearance von 50 ml/min oder weniger
    22. Jede klinisch bedeutsame neurologische, hämatologische, autoimmune, endokrine, kardiovaskuläre, neoplastische Erkrankung oder Erkrankung der Nieren oder des Magen-Darm-Trakts oder jede andere Erkrankung, die nach Ansicht des Prüfers die Teilnahme des Patienten an der Studie beeinträchtigen könnte, den Patienten einem größeren Risiko aussetzt oder zu einer Fehlinterpretation der Studienergebnisse führen könnte
    23. Der Patient ist nach Auffassung des Prüfers (aus irgendeinem Grund) nicht geeignet, TUDCA zu erhalten, oder nicht in der Lage, das Dosierungsschema einzuhalten oder den Studienuntersuchungen nachzukommen
    24. Der Patient ist sexuell aktiv und nicht bereit, während der Studie und bis zu 90 Tage nach der letzten Dosis hochwirksame Verhütungsmethoden anzuwenden
    25. Der Patient ist schwanger oder stillt
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint is measured through identification of the responder patients defined as those showing an improvement of at least 20% in the ALSFRS-R slope during the 18 months compared to the lead-in period. For each randomised patient, slope coefficients of ALSFRS-R are calculated by linear regression models sep-arately during the lead-in period and during the 18 months of treatment period
    E.5.1.1Timepoint(s) of evaluation of this end point
    This endpoint will be evaluate during the initial observation period and during the 18 months of the treatment period.
    E.5.2Secondary end point(s)
    • Survival time measured by death or respiratory insufficiency (DRI; defined as
    tracheostomy or the use of non-invasive ventilation for =22 h per day for =10
    consecutive days).
    • Difference in change from baseline in disease progression and functional impairment
    between TUDCA and placebo over 18 months (as measured by ALSFRS-R, ALSAQ-40
    questionnaire 33, Forced Vital Capacity 34, EQ-5D scale 35 and MRC sum-score 36).
    • Long-term safety and tolerability of TUDCA treatment in patients with ALS for up to
    18 months (as assessed through adverse reaction, concomitant treatment, physical
    examination, vital signs and routine haematology and biochemistry analyses).
    • Effect of TUDCA on biomarkers of disease progression (such as CSF and serum
    Neurofilament levels, serum MMP-9 expression and plasma creatinine levels 37) over 18
    months in comparison to placebo.
    E.5.2.1Timepoint(s) of evaluation of this end point
    All efficacy and safety endpoints will be compared between the two randomization
    groups at the end of the study
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA19
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 250
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 290
    F.4.2.2In the whole clinical trial 320
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients who have completed the full 18-month term of the TUDCA-ALS trial will be offered the possibility for participation in an open-label extension study, without knowing whether they had been allocated to the active or reference therapy..
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-05-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-03
    P. End of Trial
    P.End of Trial StatusCompleted
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